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Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study
Journal article   Open access

Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study

Xiangrong Cui, Xuan Jing, Susan K Lutgendorf, Catherine S Bradley, Andrew Schrepf, Bradley A Erickson, Vincent A Magnotta, Timothy J Ness, Karl J Kreder, Michael A O'Donnell, …
American journal of physiology. Renal physiology, Vol.317(1), pp.F90-F98
07/01/2019
DOI: 10.1152/ajprenal.00017.2019
PMCID: PMC6692719
PMID: 31091120
url
https://doi.org/10.1152/ajprenal.00017.2019View
Published (Version of record) Open Access

Abstract

Altered Toll-like receptor (TLR)4 activation has been identified in several chronic pain conditions but has not been well studied in interstitial cystitis/bladder pain syndrome (IC/BPS). Our previously published human studies indicated that patients with IC/BPS present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In the present study, we sought to determine whether altered TLR4 activation plays a role in pelvic/bladder pain seen in patients with IC/BPS using our validated IC/BPS-like transgenic autoimmune cystitis model (URO-OVA). URO-OVA mice developed responses consistent with pelvic and bladder pain after cystitis induction, which was associated with increased splenocyte production of TLR4-mediated proinflammatory cytokines IL-1β, IL-6, and TNF-α. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-α, glial activation markers CD11b and glial fibrillary acidic protein, and endogenous TLR4 ligand high mobility group box 1 was also observed after cystitis induction. Compared with URO-OVA mice, TLR4-deficient URO-OVA mice developed significantly reduced nociceptive responses, although similar bladder inflammation and voiding dysfunction, after cystitis induction. Intravenous administration of TAK-242 (a TLR4-selective antagonist) significantly attenuated nociceptive responses in cystitis-induced URO-OVA mice, which was associated with reduced splenocyte production of TLR4-mediated IL-1β, IL-6, and TNF-α as well as reduced spinal expression of mRNAs for IL-6, TNF-α, CD11b, glial fibrillary acidic protein, and high mobility group box 1. Our results indicate that altered TLR4 activation plays a critical role in bladder nociception independent of inflammation and voiding dysfunction in the URO-OVA model, providing a potential mechanistic insight and therapeutic target for IC/BPS pain.
 Analgesics - pharmacology Autoimmune Diseases - physiopathology Spleen - immunology Ovalbumin - immunology Spine - metabolism Cystitis, Interstitial - physiopathology Autoimmune Diseases - genetics Nociceptive Pain - metabolism Ovalbumin - metabolism Inflammation Mediators - metabolism Nociceptive Pain - genetics Pain Threshold - drug effects Spine - immunology Toll-Like Receptor 4 - antagonists & inhibitors Autoimmune Diseases - metabolism Cytokines - genetics Cystitis, Interstitial - metabolism Disease Models, Animal Ovalbumin - genetics Cytokines - metabolism Nociceptive Pain - immunology Signal Transduction Urinary Bladder - metabolism Mice, Inbred C57BL Autoimmune Diseases - immunology Cells, Cultured Toll-Like Receptor 4 - genetics Urinary Bladder - immunology Toll-Like Receptor 4 - immunology Sulfonamides - pharmacology Toll-Like Receptor 4 - metabolism Mice, Knockout Urodynamics Animals Cystitis, Interstitial - immunology Nociceptive Pain - physiopathology Spleen - metabolism Cystitis, Interstitial - genetics Urinary Bladder - physiopathology Urinary Bladder - drug effects

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